Capsules containing high doses of levodopa for pulmonary use

ABSTRACT

The present invention provides a capsule containing an inhalable powder composition wherein the composition comprises about 75% by weight or more levodopa, dipalmitoylphosphatidylcholine (DPPC) and a salt characterized by a working density of less than about 100 g/L. The invention further provides a capsule containing an inhalable powder composition wherein the composition comprises about 75% by weight or more levodopa, dipalmitoylphosphatidylcholine (DPPC) and a salt characterized by a working density of less than about 100 g/L wherein the capsule material comprises hydroxypropylmethylcellulose (HPMC) and titanium dioxide.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/724,781, filed on Nov. 9, 2012. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Parkinson's disease is a debilitating disease caused by the death ofdopamine neurons in the central nervous system. Parkinson's diseasepatients experience life altering symptoms of tremors, slowness inmoving, and difficulty walking. While no drugs exist which cure thedisease or stop its progression, a number of drugs exist to help withsymptoms. The most commonly used drug and the drug all Parkinson'spatients eventually use is levodopa. Levodopa (also referred to hereinas “levodopa”) is currently supplied in tablets with or without one ortwo other drugs. The other drugs typically function to prevent the bodyfrom metabolizing the levodopa before it can take its effect. Manypatients initially respond well to levodopa treatment, but over time theeffect becomes diminished. Patients typically start increasing theirlevodopa dosage as their disease progresses. A patient at the earlystages of taking levodopa may only take 200 mg of levodopa per day, buta later stage patient could be taking 600 to 1200 mg of levodopa a day.Once the doses increase, patients become prone to dyskinesias.Dyskinesias are involuntary movements due to too much levodopa. Whenpatient levodopa concentrations go to low, patients experience freezingepisodes where the patient has significant difficulty moving. Once afreezing episode occurs, patient can take a tablet of levodopa, but theyhave to wait until the levodopa is absorbed to become unfrozen. Furthercomplicating the freezing problem is that Parkinson's patients have poorstomach motility resulting in slow drug absorption. An inhalableformulation of levodopa could help patients with these freezing issues.A difficulty in creating an inhalable levodopa product is deliveringenough dose to the patient, since levodopa is a high dose drug. Anotherdifficulty is delivering an inhaled drug to a Parkinsons' patient. Sincethese patients are movement impaired, they need a quick and simpleprocess to inhale the levodopa.

In addition to the above difficulties with delivering levodopa, a numberof difficulties exist with delivering high doses of any drug by thepulmonary route. A dry powder containing a drug can vary greatly indensity. Modifying the density of the powder can affect stability andthe ability of the drug to reach the lungs appropriately. However,optimizing the density of the levodopa inhalable powder enables theeffective delivery of high doses of levodopa to the patient byinhalation. Even if appropriate density can be reached for a high dosedrug such as levodopa, the efficient emptying of the powder from thecapsule is also a critical factor. If the emptying characteristics ofthe capsule are poor, the increased dosage achieved by optimal loadingof the powder into the capsule is diminished.

A number of important challenges exist to deliver a high dose oflevodopa to a Parkinson's patient while also keeping the drug productstable and easy to use for the patient. Pulmonary powders may beprovided in amorphous form as amorphous forms of a compound have fasterdissolution and would be more likely to show a fast onset of action.Despite the advantage of fast onset of action for an amorphous powder,amorphous powders are difficult to manufacture and difficult to keepstable under long term storage conditions, as required by the drugregulatory agencies. Further, filling large volumes of amorphous powdersin a capsule can be challenging due to electrostatic charges. Forcrystalline powders, increasing the relative humidity can reduce theelectrostatic charge of the powder and allow for better capsule filling,but increasing the relative humidity is not a viable option for anamorphous powder. Amorphous powders become prone to amorphous tocrystalline transitions under elevated relative humidity. Thus, asignificant difficulty exists in identifying a fast acting amorphouspowder which is stable with a low electrostatic charge.

SUMMARY OF THE INVENTION

The present invention provides a capsule containing an inhalable powdercomposition wherein the composition comprises about 75% by weight ormore levodopa, dipalmitoylphosphatidylcholine (DPPC) and a saltcharacterized by a working density of less than about 0.1 g/cm³. Theinvention further provides a capsule containing an inhalable powdercomposition wherein the composition comprises about 75% by weight ormore levodopa, dipalmitoylphosphatidylcholine (DPPC) and a saltcharacterized by a working density of less than about 0.1 g/cm³ whereinthe capsule material comprises hydroxypropylmethylcellulose (HPMC) andtitanium dioxide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a purge gas humidification setup using pressurepot FIG. 2A is a schematic of a standard versus setup for introductionof purge gas.

FIG. 2B is a schematic of an angled setup for introduction of purge gas.

FIG. 3A is a schematic of an angled-inlet purge set up with a 0°downward facing purge stream.

FIG. 3B is a schematic of an angled-inlet purge set up with a 0° upwardfacing purge stream.

FIG. 3C is a schematic of an angled-inlet purge set up with a 25-30°downward facing purge stream.

FIG. 3D is a schematic of an angled-inlet purge set up with a 25-30°upward facing purge stream.

FIG. 4 is a schematic of the side view of a full bore dosator setup.

FIG. 5 is a schematic of the process steps in capsule filling operationutilizing the full bore dosator. The process is shown in five steps.Step 1 shows the dosator immersed into the powder bed. Step 2 shows thevacuum applied to the dosator that pulls the powder into the dosator.Step 3 shows the vacuum application contined, and the dosater moved fromthe powder bed to the capsule filling station. Step 4 shows the vacuumapplication continued and the dosater positioned above an empty capsulein the capsule filling station. Step 5 shoes the vacuum discontinued andexplusion pressure applied to the dosator expelling the powder from thedosator into the empty capsule thereby filling the capsule.

DETAILED DESCRIPTION OF THE INVENTION

The capsules according to the invention are for use in an inhalationdevice and contain, as the inhalable powder, levodopa mixed with one ormore physiologically acceptable excipients, characterized in that thepowder has a working density (also referred to herein as “bulk density”)of about 100 g/L or less which can also be expressed as about 0.1 g/cm³or less. Because levodopa is a high dose drug and delivering largeamounts of levodopa is difficult for pulmonary delivery, it would bedesirable to have a low density powder. A low density powder could allowfor a significantly higher dose of levodopa per capsule than an averagedensity powder. A difficulty is that low density levodopa powders aredifficult to achieve while still allowing for a powder that can beeasily filled into a capsule. In one embodiment the invention providescapsules containing an inhalable powder comprising levodopa wherein thecapsule has superior emptying characteristics upon delivery of thepowder from the capsule upon actuation when used in conjunction with aninhaler. Superior emptying from the capsule is an importantcharacteristic of a capsule containing an inhalable powder comprisinglevodopa.

The capsules for inhalation according to the invention are filled withinhalable powder containing levodopa, wherein that the powder has aworking density of less than about 0.1 g/cm³ and preferably has aworking density of between about 0.02 g/cm³ and 0.08 g/cm³.

The term “working density” as used herein is interchangeable with theterm “bulk density” and is defined herein as the weight of the powder(m) divided by the volume it occupies (Vo) and is expressed herein asgrams per liter (g/L) as determined by measurement in a graduatedcylinder. Briefly, a graduated cylinder is first weighed, filled withpowder without compacting, leveled if necessary without compacting andweighed again. The unsettled apparent volume is read to the nearestgraduated unit. The working density is calculated by the formula m/Vo.Working density may also be expressed for example in grams per cubiccentimeter (g/cm³). In one embodiment the working density is less than0.1 g/cm³. In one embodiment the working density ranges from about 0.02g/cm³ to about 0.05 g/cm³.

In one embodiment, the capsules contain powder with a working densitybetween about 0.03 g/cm³ to about 0.06 g/cm³. In another embodiment, thecapsules contain powder with a working density between about 0.04 g/cm³to about 0.05 g/cm³. In a further embodiment, the capsules containpowder with a working density of about 0.04 g/cm³. In a furtherembodiment, the capsules contain powder with a working density of about0.045 g/cm³. In a further embodiment, the capsules contain powder with aworking density of about 0.05 g/cm³. In a further embodiment, thecapsules contain powder with a working density of about 0.035 g/cm³. Ina further embodiment, the capsules contain powder with a working densityof about 0.03 g/cm³. In one embodiment, the capsules contain powder witha working density between about 0.03 g/cm³ to about 0.05 g/cm³. Inanother embodiment, the capsules contain powder with a working densitybetween about 0.04 g/cm³ to about 0.06 g/cm³. In another embodiment, thecapsules contain powder with a working density between about 0.05 g/cm³to about 0.06 g/cm³. In another embodiment, the capsules contain powderwith a working density between about 0.06 g/cm³ to about 0.07 g/cm³.

The inhalable powder contained in the capsules of the inventioncomprises at least 50% by weight levodopa by weight of solids in thepowder. In some embodiments, the inhalable powder in a capsule of thisinvention may contain at least 60%, 70%, 80%, 90% by dry weight or morelevodopa. In one embodiment the inhalable powder contains about 75% bydry weight or more levodopa. In one embodiment, the inhalable powdercontains about 85% by dry weight by weight or more levodopa. In oneembodiment the inhalable powder in the capsule contains about 90% by dryweight by weight or more levodopa. In one embodiment, the inhalablepowder in the capsule contains between 80-95% by dry weight levodopa ofsolids in the powder. In one embodiment, the inhalable powder in thecapsule contains between 85-95% by dry weight levodopa of solids in thepowder. In one embodiment, the inhalable powder in the capsule containsbetween 88-92% by dry weight levodopa of solids in the powder.

The inhalation powder may contain additional excipients. Examples ofexcipients include salts such as sodium chloride (NaCl), sodium citrate,sodium lactate, and potassium chloride and phospholipids such asdipalmitoylphosphatidylcholine (DPPC) dilauroylphosphatidylcholine(DLPC), disaturated-phosphatidylcholine (DSPC). In one embodiment, thecapsule contains a powder comprising 90% levodopa, 8%dipalmitoylphosphatidylcholine, and 2% sodium chloride as measured by %of solids in the powder. In one embodiment the capsule contains aninhalable powder having a dry weight ratio of 90:8:2 oflevodopa:DPPC:NaCl. In another embodiment the capsule contains aninhalable powder having a dry weight ratio of 90:5:5 oflevodopa:DPPC:NaCl.

The capsules of the invention comprising the inhalable powders areuseful for delivery of levodopa to the pulmonary system, in particularto the deep lung. The inhalable powder contained in the capsule of theinvention is characterized by a fine particle fraction (FPF), geometricand aerodynamic dimensions and by other properties, as further describedbelow.

Gravimetric analysis, using Cascade impactors, is a method of measuringthe size distribution of airborne particles. The Andersen CascadeImpactor (ACI) is an eight-stage impactor that can separate aerosolsinto nine distinct fractions based on aerodynamic size. The size cutoffsof each stage are dependent upon the flow rate at which the ACI isoperated. Preferably the ACI is calibrated at 60 L/min. In oneembodiment, a two-stage collapsed ACI is used for particle optimization.The two-stage collapsed ACI consists of stages 0, 2 and F of theeight-stage ACI and allows for the collection of two separate powderfractions. At each stage an aerosol stream passes through the nozzlesand impinges upon the surface. Particles in the aerosol stream with alarge enough inertia will impact upon the plate. Smaller particles thatdo not have enough inertia to impact on the plate will remain in theaerosol stream and be carried to the next stage.

The ACI is calibrated so that the fraction of powder that is collectedon a first stage is referred to herein as “fine particle fraction” or“FPF”. The FPF corresponds to the percentage of particles that have anaerodynamic diameter of less than 5.6 μm. The fraction of powder thatpassed the first stage of the ACI and is deposited on the collectionfilter is referred to as “FPF(3.4)”. This corresponds to the percentageof particles having an aerodynamic diameter of less than 3.4 μm.

The FPF fraction has been demonstrated to correlate to the fraction ofthe powder that is deposited in the lungs of the patient, while theFPF(3.4) has been demonstrated to correlate to the fraction of thepowder that reaches the deep lung of a patient. In accordance with theinvention, the FPF of the inhalable powder of the nominal dose containedin the capsule (i.e. the percentage of particles in the powder containedin the capsule that have an aerodynamic diameter of less than 5.6 μm) isabout 40% or more. In one embodiment the FPF of the nominal dose of theinhalable powder contained in the capsule is about 50%, 60%, or 70%, or80%, or 90%. In one embodiment the FPF is about 50% to about 60% of thenominal dose of the inhalable powder contained in the inhaler. In oneembodiment the FPF is about 55% to about 65% of the nominal dose of theinhalable powder contained in the inhaler. In one embodiment the FPF isabout 50% to about 70% of the nominal dose of the inhalable powdercontained in the inhaler. In one embodiment the FPF is about 57% toabout 62% of the nominal dose of the inhalable powder contained in theinhaler. In one embodiment the FPF is about 50% to about 69% of thenominal dose of the inhalable powder contained in the inhaler. In oneembodiment the FPF is about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, or 65% of the nominal dose of theinhalable powder contained in the inhaler.

As used herein, the term “nominal powder dose” is the total amount ofpowder held in the capsule. As used herein, the term “nominal drug dose”is the total amount of Levodopa contained in the nominal amount ofpowder. The nominal powder dose is related to the nominal drug dose bythe load percent of drug in the powder.

In one embodiment, the nominal powder dose is 25-50 mg by dry weight. Ina further embodiment, the nominal powder dose is 25-40 mg by dry weight.In a still further embodiment, the nominal powder dose is 30-35 mg bydry weight or 32-38 mg by dry weight.

Another method for measuring the size distribution of airborne particlesis the multi-stage liquid impinger (MSLI). The Multi-stage liquidImpinger (MSLI) operates on the same principles as the Anderson CascadeImpactor (ACI), but instead of eight stages there are five in the MSLI.Additionally, instead of each stage consisting of a solid plate, eachMSLI stage consists of an methanol-wetted glass frit. The wetted stageis used to prevent bouncing and re-entrainment, which can occur usingthe ACI. The MSLI is used to provide an indication of the flow ratedependence of the powder. This can be accomplished by operating the MSLIat 30, 60, and 90 L/min and measuring the fraction of the powdercollected on stage 1 and the collection filter. If the fractions on eachstage remain relatively constant across the different flow rates thenthe powder is considered to be approaching flow rate independence.

In one embodiment, the inhalable powders of the invention have a tapdensity of less than about 0.4 g/cm³. For example, the particles have atap density less than about 0.3 g/cm³, or a tap density less than about0.2 g/cm³, a tap density less than about 0.1 g/cm³. Tap density can bemeasured by using instruments known to those skilled in the art such asthe Dual Platform Microprocessor Controlled Tap Density Tester (Vankel,N.C.) or a GEOPYC™ instrument (Micrometrics Instrument Corp., Norcross,Ga., 30093). Tap density is a standard measure of the envelope massdensity. Tap density can be determined using the method of USP BulkDensity and Tapped Density, United States Pharmacopia convention,Rockville, Md., 10^(th) Supplement, 4950-4951, 1999. Features which cancontribute to low tap density include irregular surface texture andporous structure. The envelope mass density of an isotropic particle isdefined as the mass of the particle divided by the minimum sphereenvelope volume within which it can be enclosed. In one embodiment ofthe invention, the particles have an envelope mass density of less thanabout 0.4 g/cm³.

The inhalable powder of the invention has a preferred particle size,e.g., a volume median geometric diameter (VMGD) of at least about 1micron (μm). The diameter of the spray-dried particles, for example, theVMGD, can be measured using a laser diffraction instrument (for exampleHelos, manufactured by Sympatec, Princeton, N.J.). Other instruments formeasuring particle diameter are well known in the art. The diameter ofparticles in a sample will range depending upon factors such as particlecomposition and methods of synthesis. The distribution of size ofparticles in a sample can be selected to permit optimal deposition totargeted sites within the respiratory tract.

The particles of the inhalable powder of the invention preferably have a“mass median aerodynamic diameter” (MMAD), also referred to herein as“aerodynamic diameter”, between about 1 μm and about 5 μm or anysubrange encompassed between about 1 μm and about 5 μm. For example, butnot limited to, the MMAD is between about 1 μm and about 3 μm, or theMMAD is between about 3 μm and about 5 μm. Experimentally, aerodynamicdiameter can be determined by employing a gravitational settling method,whereby the time for an ensemble of powder particles to settle a certaindistance is used to infer directly the aerodynamic diameter of theparticles. An indirect method for measuring the mass median aerodynamicdiameter (MMAD) is the multi-stage liquid impinger (MSLI). Theaerodynamic diameter, d_(aer), can be calculated from the equation:d_(aer)=d_(g)√ρ_(tap)where d_(g) is the geometric diameter, for example the MMGD, and ρ isthe powder density.

In one embodiment, the particles have a mass mean geometric diameter(MMGD) of between about 5 μm and about 18 μm. In another embodiment, theparticles have a mass mean geometric diameter (MMGD) of between about 5μm and about 12 μm. In another embodiment, the particles have a massmean geometric diameter (MMGD) of between about 8 μm and about 10 μm. Inanother embodiment, the particles have a mass mean geometric diameter(MMGD) of between about 8 μm and about 15 μm.

Powders for use in capsules of this invention are typically produced byspray drying. In some cases, spray-drying can produce extremely dryparticles which may have poor handling properties and may be difficultto compact into a capsule in a dense manner. A nitrogen source with aspecified moisture level may be flown over, across, or through the drypowder to add a specific moisture content to the dry powder. Suchmoisture can provide the desired working density of the powder. Spraydrying methods in accordance with the invention are described in theExamples herein and in U.S. Pat. Nos. 6,848,197 and 8,197,845,incorporated herein by reference.

The inhalable powder comprising levodopa as described above is used tofill capsules suitable for use in an inhaler. The term “capsulematerial” as used herein refers to the material from which the shell ofthe capsule for inhalation is made. In one embodiment, the capsulematerial according to the invention is selected from among gelatin,cellulose derivatives, starch, starch derivatives, chitosan andsynthetic plastics.

If gelatin is used as the capsule material, examples according to theinvention may be selected from among polyethyleneglycol (PEG), PEG 3350,glycerol, sorbitol, propyleneglycol, PEO-PPO block copolymers and otherpolyalcohols and polyethers. If cellulose derivatives are used as thecapsule material, examples according to the invention may be selectedfrom hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. Ifsynthetic plastics are used as the capsule material, examples accordingto the invention may be selected from polyethylene, polycarbonate,polyester, polypropylene and polyethylene terephthalate. In oneembodiment, the capsule material further comprises titanium dioxide. Inone preferred embodiment the capsule comprises HPMC and titaniumdioxide. In one embodiment, the capsule comprises carrageenan. In afurther embodiment, the capsule comprises potassium chloride. In a stillfurther embodiment, the capsule comprises, HPMC, carrageenan, potassiumchloride, and titanium dioxide. In one embodiment, the capsule size isselected from 000, 00, 0, 1, or 2. In a specific embodiment, the capsulesize is 00.

In one specific embodiment, the capsule is ahydroxypropylmethylcellulose (HPMC) capsule. In another specificembodiment, the capsule is a hydroxypropylmethylcellulose size 00capsule. In one specific embodiment the capsule material comprises HPMCand titanium dioxide and the capsule size is 00.

In one embodiment, a 00 capsule contains between 15 and 50 milligrams oflevodopa by dry weight. In another embodiment, a 00 capsule containsbetween 20 and 40 milligrams of levodopa by dry weight. In anotherembodiment, a 00 capsule contains between 25 and 35 milligrams oflevodopa by dry weight. In another embodiment, a 00 capsule containsabout 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 milligrams oflevodopa by dry weight.

In one aspect of the invention, the powders have low electrostaticcharge to enable high dispersion from the capsule.

The capsules of the invention are particularly suitable for use in a drypowder inhaler for the delivery of a dry powder composition comprisinglevodopa to a patient afflicted with, for example, Parkinson's diseaseand in need of treatment with levodopa. The patient in need of treatmentmay require maintenance therapy for Parkinson's disease or rescuetherapy for Parkinson's disease such as would be necessary in the caseof an acute and/or freezing episode due to Parkinson's disease. In oneembodiment, the capsules are used in a dry powder inhaler to deliver aneffective amount of the dry powder composition to the patient in asingle breath as is described in U.S. Pat. Nos. 6,858,199 and 7,556,798incorporated herein by reference.

As used herein, the term “effective amount” means the amount needed toachieve the desired effect or efficacy. The actual effective amounts ofdrug can vary according to the specific drug or combination thereofbeing utilized, the particular composition formulated, the mode ofadministration, and the age, weight, condition of the patient, andseverity of the episode being treated. In the case of a dopamineprecursor, agonist or combination thereof it is an amount which reducesthe Parkinson's symptoms which require therapy. Dosages for a particularpatient are described herein and can be determined by one of ordinaryskill in the art using conventional considerations, (e.g. by means of anappropriate, conventional pharmacological protocol). For example,effective amounts of oral levodopa range from about 50 milligrams (mg)to about 500 mg. In many instances, a common ongoing (oral) levodopatreatment schedule is 100 mg eight (8) times a day.

The administration of more than one dopamine precursor, agonist orcombination thereof, in particular levodopa, carbidopa, apomorphine, andother drugs can be provided, either simultaneously or sequentially intime. Carbidopa or benserazide, for example, is often administered toensure that peripheral carboxylase activity is completely shut down.Intramuscular, subcutaneous, oral and other administration routes can beemployed. In one embodiment, these other agents are delivered to thepulmonary system. These compounds or compositions can be administeredbefore, after or at the same time. In a preferred embodiment, particlesthat are administered to the respiratory tract include both Levodopa andcarbidopa. The term “co-administration” is used herein to mean that thespecific dopamine precursor, agonist or combination thereof and/or othercompositions are administered at times to treat the episodes, as well asthe underlying conditions described herein.

In one embodiment chronic levodopa therapy includes the use of thecapsules of the invention in a dry powder inhaler for pulmonary deliveryof levodopa combined with oral carbidopa. In another embodiment,pulmonary delivery of levodopa is provided during the episode, whilechronic treatment can employ conventional oral administration oflevodopa/carbidopa. In a further embodiment chronic levodopa therapyincludes the use of the capsules of the invention in a dry powderinhaler for pulmonary delivery of levodopa combined with oralbenserazide. In another embodiment, pulmonary delivery of levodopa isprovided during the episode, while chronic treatment can employconventional oral administration of levodopa/benserazide.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1

This example summarizes a series of studies examining modificationsperformed on the spray drying operation for the production of a 90:8:2levodopa:dipalmitoylphosphatidylcholine (DPPC):sodium chloride (NaCl)composition referred to herein as “90:8:2”. The 90:8:2 spray dryingoperation that was developed for the production of initial lots ofpowders containing levodopa involved the production of a 90:8:2levodopa: DPPC: NaCl powder that was fully amorphous with a watercontent of approximately 4%, a fine particle fraction in the range of50-60%<5.4 microns and a maximum capsule fill weight of approximately 23mg per size 00 capsule. This combination of properties resulted in amaximum delivered dose of levodopa (fine particle mass of levodopa) ofapproximately 12 mg per capsule, with these powders exhibiting a highdegree of electrostatic charging and low bulk (typically 0.01-0.02 g/cc)and tap density (typically 0.02-0.04 g/cc), which made it extremelydifficult to fill these powders reproducibly into size 00 capsules.Based on this, it was desired to attempt to increase the delivered doseof levodopa per capsule to 17 mg or greater. Additionally, it wasdesired to increase the physical stability of the 90:8:2 powder, as somepowder lots were also observed to undergo an amorphous to crystallineconversion upon storage, particularly for lots that were filled underconditions for which the laboratory humidity was not controlled, thuspotentially exposing these lots to elevated humidity.

During the spray drying operation, powder collected on the filter bagsin the product filter is exposed to the moisture-laden environment ofthe product filter because of water vapor moving from the spray dryingunit towards the exhaust across the product filter bags. When thispowder is pulsed off the filter bags for collection, it tends to retainthe residual moisture that it picked up in the product filter, which mayact to facilitate a solid-state conversion from an amorphous to acrystalline form, either immediately or at some point during storage. Toprevent this conversion, the powder must be dried effectively prior tocollection, which is achieved by introducing dry nitrogen as a purgestream between the product filter and the collection vessel. However,during this drying operation, the powder becomes electrostaticallycharged, possibly due to bone dry conditions of the incoming nitrogenpurge gas. This electrostatic charge decreases the bulk density of thepowder, which in-turn decreases the amount of powder that can be filledin a capsule hence reducing the fine particle mass (FPM) per capsule.The methods and modifications indicated below were performed andevaluated for their ability to increase the FPM by eliminating theelectrostatic charge on the powder and/or increasing the bulk density ofthe powder without predisposing the powder to solid-state conversion.

The studies described herein were thus conducted with the goals of (1)optimizing the fine particle mass (FPM) per capsule, (2) increasing thecapsule fill weight and (3) stabilizing the amorphous solid statestructure of bulk spray dried 90:8:2. Process parameter, unit operationand formulation modifications were executed and evaluated for theireffectiveness in achieving endpoints (1-3).

Types of Modifications

Three types of modifications, (1) unit operation modifications, (2)process parameter modifications and (3) formulation modifications wereevaluated.

(1) Unit Operation Modifications

Two types of unit operation modifications were studied, (i) the use ofhumidified purge gas and (ii) in-line ionization. Of these two, the useof humidified purge gas showed the best results with respect todecreasing electrostatic charge and increasing the maximum fill weightof the capsules. The details of this modification are described below.

Exposure to a humid environment helps decrease the static charge storedon a material because moisture in the air increases the conductivity ofair, thereby enabling gas discharge. Since the dry nitrogen used as thepurge gas to dry the powder was thought to be the primary cause forgeneration of the electrostatic charge on the 90:8:2 powderhumidification of the purge gas may allow for charge dissipation andhelp eliminate the electrostatic charge stored on the surface of thepowder particles. This can act to increase the bulk density, which willin-turn increase the fine particle mass per capsule.

Humidification of the purge gas was carried out using two types of purgeinlet setups (i) a standard inlet setup as shown in FIG. 2A, in whichthe purge gas entered the product filter horizontally in at the bottomof the product filter and (ii) an angled inlet setup as shown in FIG.2B, in which the purge gas enters the product filter at an angle to thevertical axis at the bottom of the product filter.

In a standard configuration, the powder pulsed off the product filterbags has contact with the dry purge gas for only a fraction of a seconddue to the narrow stream of purge gas entering in such a setup. Bychanging the angle of the purge gas inlet, as in the angled inletconfiguration, one can increase the exposure time for powder pulsed offthe bags to incoming dry purge gas. This setup may help more efficientelimination static charging as compared to a humidifying purge gascoming in through a standard horizontal inlet, which in turn mayincrease the fine particle mass and decrease the electrostatic chargingof the powder.

Referring to FIG. 1A, humidification of the purge gas was carried out bypassing the gas through a pressure pot 1 filled with water 2 forirrigation. A bypass line 3 with a control valve 8 was attached inparallel with the pressure pot 1. By controlling the ratio of the amountof nitrogen that passes through the pressure pot 1 to the amount thatbypasses it, one can control the resulting relative humidity (RH) of thepurge gas. Humidity of the exiting purge gas was measured using adew-point meter 4 attached in series downstream of the humidificationpressure pot 1 apparatus.

The purge gas is then passed through rotameter 5 which functions tocontrol the flow of the purge gas to the product filter and facilitatesadjusting the water content of the final powder. Butterfly valve 31functions to isolate the product filter from the environment when thecollection vessel 7 is changed. Butterfly valve 32 functions to isolatethe collection vessel from the environment during the product transferstep from the collection vessel into a holding container which is storedat optimized temperature and relative humidity.

The humidified purge gas was then introduced at the bottom of theproduct filter apparatus 6 through (i) standard horizontal purge inlet(FIG. 2A), or (ii) angled purge inlet setup (FIG. 2B).

In an angled inlet setup (FIG. 2B), a directional inlet 9 for the purgegas stream was used, as opposed to a standard horizontal inlet 10 (FIG.2A). This directional inlet 9 can be rotated along its own axis, and canhence be directed towards either the product filter 6 or the collectionvessel 7 as shown in FIG. 1 and FIGS. 3A-D.

Directional inlet 9 configurations used included: downward 0° (FIG. 3A),upwards 0° (FIG. 3B), downwards angled 25-30° (FIG. 3C) and upwardsangled 25-30° (FIG. 3D) with items in parenthesis indicating the angleto the vertical axis of the product filter.

Additionally, with the purge gas inlet at 0° to the vertical axis,different atomization gas flow (25 g/min to 55 g/min) rates wereevaluated.

Experimental Conditions

Purge gas was humidified to different relative humidity levels.Rotameter for purge gas inlet was set to 3.5 g/min or 20 scfh.

Results

Standard Setup

Powders generated using nitrogen purge gas humidified to different RHswere observed to have similar particle sizes and fine particle fractionsas compared to the powders manufactured under standard purge gascondition of 0% relative humidity (Table 1).

TABLE 1 FPF and geometric particle size distribution (gPSD) results forpowders produced using different purge relative humidities. Purge gasFine particle humidification (% RH) fraction (%) gPSD (μm) 10% RH(02098-1) 57% 7.6 20% RH (02096-0) 54% 5.3 40% RH (02098-2) 52% 7.8

However, visual observation of the powders indicated that the powderswere much denser compared to the standard powder. Additionally, X-raypowder diffraction (XRPD) analysis of these powders showed evidence ofcrystalline peaks starting to form for the powders produced with purgegas humidities in excess of 10%. It is expected that this initial amountof crystalline phase will act to catalyze further recrystallization ofthese powders upon storage, which has been observed to result inundesirable decreases in FPF and water content. Thus, it was determinedthat a purge gas humidification in the range of 5-10% RH was optimalwith respect to decreasing the electrostatic charge of the spray-driedpowders utilizing the standard setup.

Angled Setup

The results obtained from the use of different orientations of the purgegas inlet and constant atomization gas flow rates are summarized inTable 2 below.

TABLE 2 FPF for different purge gas inlet orientations with constantatomization gas flow rate (22 g/min). Purge gas orientation (and Purgegas relative FPF Water angle to the vertical axis) humidity (%) (%)content (%) Downwards (0°) 20 Too much static charge Upwards (0°) 15 543.35 Downwards angled 10 34 3.32 (25-30°) #1 Downwards angled 10 53 3.52(25-30°) #2 Upwards angled (25-30°) #1 10 53 3.91 Upwards angled 10 533.89 (25-30°) #2

The powder produced with a downward angled orientation could not besampled due to the very high electrostatic charge present when thecollection vessel was opened for sampling.

The results obtained from the use a single orientation of the purge gasinlet and a different atomization gas flow rates are summarized in Table3 below.

TABLE 3 FPF for upward facing purge gas inlet orientation with differentatomization gas flow rates. Purge gas orientation Atomization Water(Angle to the vertical gas flow rate FPF content axis and RH) (g/min)(%) (%) Upwards (0° at 10% RH) 25 49 4.01 Upwards (0° at 10% RH) 35 553.88 Upwards (0° at 10% RH) 45 56 3.95 Upwards (0° at 10% RH) 55 48 3.85Upwards (0° at 10% RH) 30 55 2.64

Visually, all powders except for the one produced with downward angledorientation appeared to be much denser and to possess a relatively lessamount of electrostatic charge as compared to the powders produced withthe standard purge gas inlet orientation.

Results

Although humidification of the purge gas was observed to make thepowders denser while keeping the FPF and water content the same, theseformulations were observed in some cases to display evidence of theformation of a crystalline phase via XRPD, in particular for purge gashumidities in excess of 10%. As a result, the use of purge gashumidified to greater than 10% RH was determined to not be a viableoption, with the use of a purge gas relative humidity in the range of 5to 10% providing a mechanism for reducing powder electrostatic chargeand increasing powder density without decreasing powder FPF or causingan amorphous to crystalline conversion.

(2) Formulation Modifications

Alternative formulations to the 90:8:2 levodopa:DPPC:NaCl powder wereevaluated for their effectiveness in optimizing the FPF, fill weight andsolid state stability.

Modification of DPPC: Sodium Chloride Ratio

Powders having an alternate ratio of DPPC:NaCl were evaluated for theirefficiency in increasing the density and reducing electrostatic chargingof the 90% levodopa powders. It was hypothesized that increasing thesalt content of the powders could potentially act to help dissipate andthus reduce their electrostatic charge.

Experimental Design:

A DPPC:NaCl ratio of 4:6 was initially selected as a starting point toevaluate the influence of a higher amount of sodium chloride on the FPFand density of the 90:8:2 powders. Purge gas relative humidities weremaintained at both 0% and 10%.

Results:

The physical and aerodynamic properties of 90:4:6 levodopa:DPPC:NaCllots produced utilizing the standard conditions for the 90:8:2formulation are shown in Table 4.

TABLE 4 Analytical results for initial trial runs of 90:4:6levodopa:DPPC:NaCl. levodopa: Bulk Tap DPPC: Purge gas FPF gPSD densitydensity NaCl Ratio RH (%) (%) (um) (g/cc) (g/cc) 90:8:2 0 52 7.97 0.0230.042 90:4:6 0 63 6.87 0.037 0.069 90:4:6 10 50 6.49 0.04 0.075

As can be seen in Table 4, the 90:4:6 levodopa:DPPC:NaCl powdersproduced possessed bulk and tap densities substantially higher thanthose seen for 90:4:6 levodopa:DPPC:NaCl powders made using similarconditions (typically 0.02 g/cc for bulk density and 0.04 g/cc for tapdensity). Since this trial produced favorable bulk and tap densityresults along with favorable results for FPF and gPSD, a decision wasmade to evaluate additional alternative DPPC:NaCl ratios of 2:8 and 6:4and compare the results to 4:6 and control (8:2) powders. Results forpowders produced utilizing the standard conditions for the 90:8:2formulations are shown in Table 5.

TABLE 5 Analytical results for alternative DPPC:NaCl ratios compared tothe control. levodopa: Bulk Tap DPPC: FPF gPSD density density NaClratio (%) (um) (g/cc) (g/cc) 90:8:2 52 7.97 0.023 0.042 90:6:4 40 90:4:663 6.87 0.037 0.069

Since a DPPC:NaCl ratio of 4:6 was observed to produce both high FPF andhigh bulk/tap density, this formulation was replicated to check forreproducibility. Results for the repeat runs for the 90:4:6levodopa:DPPC:NaCl formulation are shown in Table 6 below.

TABLE 6 Reproducibility runs for 90:4:6 levodopa:DPPC:NaCl.levodopa:DPPC:NaCl FPF gPSD Bulk density Tap density (Run #) (%) (um)(g/cc) (g/cc) 90:4:6 (Run #1) 41 9.13 0.04 0.05 90:4:6 (Run #2) 44 0.030.04 90:4:6 (Run #3) 45 0.04 0.06 90:4:6 (Run #4) 46 6.9 0.058 0.08790:4:6 (Run #5) 53 6.4 0.055 0.091

Levodopa:DPPC:NaCl Formulations.

Based on these results, a DPPC:NaCl ratio of 5:5 was also produced andanalyzed. The fine particle fraction, bulk/tap densities and geometricparticle size for three runs of this formulation are summarized in Table7 below.

TABLE 7 Reproducibility results for 90:5:5 levodopa:DPPC:NaClformulation. levodopa:DPPC:NaCl FPF gPSD Bulk density Tap density (Run#) (%) (um) (g/cc) (g/cc) 90:5:5 (Run #1) 51 7.4 0.039 0.054 90:5:5 (Run#2) 53 7.6 0.044 0.062 90:5:5 (Run #3) 51 6.5 0.044 0.066

The 90:5:5 levodopa:DPPC:NaCl formulations show very desirable FPFvalues, which are in the same range of the standard 90:8:2levodopa:DPPC:NaCl formulation, and at the same time show desirable bulkand tap density values that were substantially increased as compared tothe 90:8:2 formulation and are in the range of previously evaluated90:4:6 levodopa:DPPC:NaCl formulation.

Addition of L-Leucine, Sodium Citrate or Calcium Chloride

The addition of excipients or substitution of excipients was alsoinvestigated as a potential route towards optimizing the FPM and bulkdensity of 90:8:2 powders. The excipients l-leucine, sodium citrate andcalcium chloride, which were available in-house, were used and evaluatedas additives or as substitutes to the excipients currently in the 90:8:2levodopa:DPPC:NaCl formulation.

Experimental Setup

Sodium citrate was evaluated as a potential alternative to Sodiumchloride, Calcium chloride was investigated as another potential saltadditive to the current formulation and 1-leucine was evaluated as apotential alternative to DPPC. When Calcium chloride was used, theamount of levodopa was reduced from 90% to 50%. The solid concentrationfor the solutions to be spray dried was maintained at 1 g/L.

Observations:

The results observed when l-leucine, sodium citrate and calcium chlorideare used as an additive or as a substitute in the formulation aresummarized in Table 8 below.

TABLE 8 Analytical results from excipient addition and substitution to90:8:2 powder. Capsule fill Tap Bulk weight FPF gPSD density densityFormulation (mg) (%) (um) (g/cc) (g/cc) 90:8:2 LDOPA: 27.1 32 7.86 0.0290.042 Leucine:NaCl 90:8:2 LDOPA: 27.3 DPPC:NaCitrate 50:25:15:10 33LDOPA:DPPC: NaCitrate:CaCl2 50:25:15:10 65 LDOPA:DPPC: NaCitrate:CaCl250:25:15:10 66 LDOPA:DPPC: NaCitrate:CaCl2Discussion

Although addition of l-leucine increased the tap and bulk densities ofthe powder, the FPF was significantly lower than that of the standard90:8:2 levodopa:DPPC:NaCl formulation.

Substitution of sodium chloride by sodium citrate in the same ratioproduced a capsule fill weight of 27.3 mg. An XRPD analysis of thepowder concluded that it maintained its amorphous state. However, noother tests could be performed, as the yield was significantly low.

Addition of sodium citrate and calcium chloride, in addition toincreasing the load of DPPC and reducing the load of Levodopa(50:25:15:10 Levodopa:DPPC:NaCitrate:CaCl₂) was observed to increase theFPF of the powder to 65%. However, XRPD analysis of the powder concludedthe presence crystal growth.

Example 2 Optimization of Capsule Filling Operations

The standard 90:8:2 formulation powder is a low density powder with ahigh electrostatic charge. Because of the high volume which the lowdensity 90:8:2 powders occupies, the amount of powder which can befilled into a capsule without affecting its aerodynamic performance isgreatly limited. When such a low density powder has a high electrostaticcharge, a high degree of variability can be seen in the fill weights ofcapsules due to the constant interaction of the charged powder with thewalls of the capsules and the filling equipment. Capsule fillingoperations for such a powder, which displays a low fill weight and highweight variability at the same time, presented a set of uniquechallenges, all of which necessitated filling equipment modificationswhich helped achieve the fill weight goals without affecting thephysical and chemical properties of the powder.

This example summarizes the experiments and modifications carried outthe optimize the powder filling operations conducted using the HarroHöfliger KFM III-C capsule filling machine for filling 90:8:2 powdersinto size 00 capsules.

Different KFM III-C variables and formulation compositions wereevaluated under different vacuum configurations for their effectivenessin achieving an optimal and reproducible fill weight with different90:8:2 formulations. Three vacuum configurations were used (i) no vacuumto the dosators, (ii) Use of pre-installed KFM vacuum to the dosators,and (iii) Use of external vacuum to the dosators. For the 90:8:2 activepowders, an external vacuum assisted size 00 full-bore vacuum dosatorwas determined to be the optimal configuration in order to achieveaccurate and reproducible fill weights on the KFM III-C capsule fillingmachine. The analysis of this set up is described below.

Filling with the Use of External Vacuum on Dosator

In this vacuum setup, a Gast vacuum pump (model #1023-101Q-G608X) wasused as a vacuum for the dosators instead of the vacuum on-board the KFMmachine.

Dosator configurations and formulation variables that were evaluated forcapsule filling accuracy and reproducibility using the external vacuumincluded:

-   -   (i) Standard size 00 vacuum dosator with 90:4:6        levodopa:DPPC:NaCl,    -   (ii) Standard size 00 vacuum dosator with 90:8:2        levodopa:DPPC:NaCl,    -   (iii) Standard size 00 vacuum dosator with 90:5:5        levodopa:DPPC:NaCl,    -   (iv) Full bore size 00 vacuum dosator with 90:8:2        levodopa:DPPC:NaCl, and    -   (v) Full bore size 00 vacuum dosator, size 4 plunging dosator        and size 5 plunging dosator with lactose monohydrate NF        Standard Size 00 Vacuum Dosator with 90:4:6 Levodopa:DPPC:NaCl:

For this experiment, the standard size 00 dosator was used to fillpowder obtained by spray drying a 90:4:6 levodopa:DPPC:NaCl formulation.The variables evaluated for fill weight accuracy in this experimentincluded—(i) leveling blade versus platform for the powder bed, and (ii)low versus high powder bed height. The results for this experiment aresummarized in Table 9 below.

TABLE 9 Average fill weights per capsule filling modification for 90:4:6using external vacuum. 90:4:6 Use of Use of Low bed High bedlevodopa:DPPC:NaCl blade platform height height Average fill weight (mg)13.45 22.10 15.96 15.18Standard Size 00 Vacuum Dosator with 90:8:2 Levodopa:DPPC:NaCl:

In this experiment, a standard size 00 dosator was used to fill 90:8:2levodopa:DPPC:NaCl formulation. The variables evaluated for fill weightaccuracy included (i) low powder bed height, (ii) use of blade and arake to break down powder in the powder bed, and (iii) high versus lowdosator vacuum. The results for this experiment are summarized in Table10.

TABLE 10 Average fill weights per capsule filling modification for90:8:2 using external vacuum. Low 90:8:2 powder bed Use of High Lowlevodopa:DPPC:NaCl height blade vacuum vacuum Average fill weight 8.3028.25 26.36 7.2 (mg)Standard Size 00 Vacuum Dosator with 90:5:5 Levodopa:DPPC:NaCl:

In this experiment, a standard size 00 dosator was used to fill 90:5:5levodopa:DPPC:NaCl formulation. In this experiment, only one variablewas evaluated for fill weight accuracy—low dosator vacuum versus a highdosator vacuum. The results for this experiment are summarized in Table11 below.

TABLE 11 Average fill weights per dosator vacuum modification for 90:5:5using external vacuum. 90:5:5 levodopa:DPPC:NaCl Fill weights Sample #High vacuum Low vacuum Average fill weights (mg) 29.2 22.06Full Bore Size 00 Vacuum Dosator with 90:8:2 and 90:5:5Levodopa:DPPC:NaCl

Referring now to FIG. 4, a full bore dosator 20 is a standard vacuumdosator which has been modified to increase the dosator chamber height.The dosator 20 was modified in such a way that the dosator plunger 22stays stationary, and powder is pulled into the dosator 20 by applying avacuum and expelled out of the dosator 20 by applying expulsion pressureas illustrated in the schematic of FIG. 5. Vacuum was generated by meansof a pump attached to the dosator 20 at the port 24 with appropriatetubing. A two (2) micron mesh 26 was added at the bottom of the plunger22 to prevent powder from crossing over and interfering with the vacuumpump and tubing. Expulsion pressure was provided by means of compressednitrogen sourced from an external storage tank.

In this experiment, a full bore vacuum dosator was used for filling90:8:2 powder which was produced using a nitrogen gas overlay on theaqueous phase. As discussed previously, the 90:5:5 90:8:2 powderformulations were observed to have almost twice the original fillweights due to increased bulk density and tap density values. Using afull-bore vacuum dosator, it was possible to produce similar high fillweights using the standard 90:8:2 90:8:2 powder.

To achieve the target capsule fill weight, the dosator chamber heightwas dialed in against a standard vacuum of −15″ Hg, until capsuleshaving sufficient accuracy and reproducibility of the desired fillweight were produced. The temperature of the room was maintained around20° C. and the relative humidity of the room was maintained around 20%R.H.

One lot of 90:8:2 levodopa:DPPC:NaCl was filled for a trial fill,followed by another lot of the same composition. After these two lotswere produced, a third lot with 90:5:5 levodopa:DPPC:NaCl was filled.All 3 lots are evaluated for the KFM's effectiveness in producing anaccurate and reproducible fill weight.

The results for this experiment are summarized in Table 12 below.

TABLE 12 Target fill weights and average fill weights for 90:8:2LDOPA:DPPC:NaCl formulation filled using a full bore vacuum dosator.Target Average Relative levodopa: fill fill standard DPPC:NaCl weight(mg) weight (mg) deviation (%) 90:08:02 35 34.49  3.40% 90:08:02 3838.26  3.50% 90:05:05 38 36.03 13.60%

Previous attempts at filling to 90:8:2 formulations resulted in amaximum fill weight of 23 milligrams per capsule. The fill weightsobtained using the full bore vacuum dosator are significantly greaterthan the previous attempts. For example, fill weights of 28 to 40 mg maybe achieved. Examples of fill weights include, but are not limited to,28-32 mg, 30-34 mg, or 35-40 mg.

Full Bore Size 00 Vacuum Dosator, Size 4 Plunging Dosator and Size 5Plunging Dosator with Lactose Monohydrate NF:

Lactose monohydrate NF was used as a placebo for the 90:8:2 formulation.The target fill weight of lactose was 10 mg.

CONCLUSION

Typical filling of large amounts of powder are uncommon for pulmonaryproducts. Applicants have identified new parameters and processes whichallow for filling large amounts of powder in a capsule for pulmonarydelivery. For the 90:8:2 active powders, an external vacuum assistedsize 00 full-bore vacuum dosator can be used in order to achieve highermaximum fill weights (up to 38 mg or higher) as compared to the previousmaximum fill weight of 23 mg seen for the 90:8:2 powder, as well asaccurate and reproducible fill weights on the KFM III-C capsule fillingmachine.

Additionally, of the three ratios of powders that were evaluated usingthis setup, the powder with an levodopa:DPPC:NaCl ratio of 90:8:2 can befilled much more accurately and reproducibly to the target fill weight,as compared to the 90:5:5 and 90:4:6 ratios.

For the Lactose placebo powder, an external vacuum assisted size 5plunger dosator is the setup of choice to achieve the desired targetweight accurately and reproducibly.

Example 3 Analysis of Capsule Materials and Emitted Dose

It was hypothesized that certain types of capsules may be useful inincreasing the emitted dose of powder. HPMC “clear” capsules andHPMC/titanium dioxide “white” capsules were chosen. Two workstationswith an inhaler configured with emitted dose tubes were provided. Clearor white capsules were filled to 28 mg with inhalable levodopa powder(dry weight ratio of 90:8:2 of levodopa:DPPC: NaCl) prepared inaccordance with Example 1 to a target load and placed in the inhaler. Ananalyst was assigned to each station and actuated the inhaler into theED tube at 28.3 L/min for 4.2 seconds and rinsed for content. The FPF ofthe content was measured using standard procedures. Analysts alsoswitched work stations and used each other's inhaler technique. Theresults are provided in the following Tables 13-20. Tables 13 and 14show the comparison of white capsule sourced from Shionogi, Inc. ascompared to the clear capsule (no titanium dioxide). Tables 15 and 16show the same study but the analysts have switched workstations and usedeach other's inhaler technique. Tables 17 and 18 are a compilation ofthe results from Tables 15 and 16. Tables 19 and 20 show the comparisonof a white capsule sourced from Capsugel as compared to the clearcapsule (no titanium dioxide).

TABLE 13 FPF_(TD) < 5.6% (N = 10 Per Analyst Per Capsule Type) FPFAnalyst 1 Analyst 2 Average White Capsule 53 49 51 Clear Capsule 46 4244

TABLE 14 FPF_(ED) < 5.6% (N = 10 per Analyst Per Capsule Type). FPFAnalyst 1 Analyst 2 Average White Capsule 54 49 52 Clear Capsule 49 4547

TABLE 15 FPF_(TD) < 5.6% (N = 5 Per Analyst Per Capsule Type) FPFAnalyst 1 Analyst 2 Average White Capsule 49 51 50 Clear Capsule 44 4042

TABLE 16 FPF_(ED) < 5.6% (N = 5 Per Analyst Per Capsule Type). FPFAnalyst 1 Analyst 2 Average White Capsule 50 52 51 Clear Capsule 47 4546

TABLE 17 FPF_(TD) < 5 .6% (N = 15 per Analyst Per Capsule Type) FPFAnalyst 1 Analyst 2 Average White Capsule 52 49 51 Clear Capsule 45 4244

TABLE 18 FPF_(ED) < 5.6% (N = 15 per Analyst Per Capsule Type). FPFAnalyst 1 Analyst 2 Average White Capsule 53 50 52 Clear Capsule 48 4547

TABLE 19 FPF total dose < 5.6% FPF Analyst 1 Analyst 2 Average WhiteCapsule 47 42 45 (n = 10) Clear Capsule 46 39 43 (n = 2)

TABLE 20 FPF emitted dose < 5.6% FPF Analyst 1 Analyst 2 Average WhiteCapsule 52 46 49 (n = 10) Clear Capsule 51 43 47 (n = 2)Discussion

The data shows that more powder was emitted from the white capsuleshaving a capsule material that comprises HPMC and titanium dioxide ascompared to the powder emitted from the clear capsules that do notcontain titanium dioxide in the capsule material. This data issurprising. Without being limited to any theory, it is believed that thetitanium dioxide present in the capsule material reduces the amount ofpowder that sticks to the capsule wall upon emptying from the capsule.

Example 4 Stability Studies

Purpose

To characterize 90/8/2 and 90/5/5 Levodopa powder in machine filledcapsules that have been exposed to 75% relative humidity and 25° C.conditions for 15, 30 and 60 minutes using gravimetric ACI-3 and XRPD.Additional time points were added at 240 and 360 minutes of exposure,white and clear capsules were tested with lot 41021 (90/8/2).

Experimental Design:

Samples from Lot 28100 (90/8/2) and Lot 28109 (90/5/5) were exposed topre-stated conditions in a humidity chamber and then immediatelyanalyzed.

TABLE 21 Data Summary (clear capsules): Lot 28100 28109 Time Exposed 1530 60 15 30 60 (minutes) Average FPF < 5.6 57 62 58 51 52 52 μm Relativeto Change in Capsule Weight (%) XRPD Results A A A A A A A = Amorphous C= Crystalline

TABLE 22 Data Summary (white vs. clear capsules): Lot 41021 41021 WhiteCapsule Clear Capsule Time Exposed 240 360 240 360 (minutes) Average FPF< 5.6 μm  24  20  23  22 Relative to Change in Capsule Weight (%) XRPDResults C C C C A = Amorphous C = CrystallineMaterials and Methods1. MaterialHand Filled 90% L-Dopa Capsules Blistered in white and clear HPMCcapsules 4 capsules per pullFilled with Lot 410182. Test ScheduleCapsules will be stored in 25° C./75% RH chamber for the times listedbelow in Table 23. Capsules will be tested with the capsule cap onduring exposure and the cap off during exposure for each type ofcapsule.

TABLE 23 Condition Time Point 30 Min 60 Min 120 Min 240 Min 25° C./ FPF,grav X X X X 75% RH (n = 1) gPSD (n = 1) X X X X XRPD (n = 1) X X X X3. Resultsa. gPSD

TABLE 24 gPSD Capsule White Clear Time White No Clear No Point Cap CapCap Cap  30 Min 8.4 8.2 8.0 8.5  60 Min 8.2 8.5 8.6 8.8 120 Min 9.5 8.78.7 8.8 240 Min 8.7 8.7 9.0 8.3b. XRPD

TABLE 25 XRPD Capsule White Clear White No Clear No Time Point Cap CapCap Cap  30 Min Amorphous Amorphous Amorphous Amorphous  60 MinAmorphous Amorphous Amorphous Amorphous 120 Min Amorphous AmorphousAmorphous Amorphous 240 Min Amorphous Amorphous Amorphous Amorphousc. % FPF<5.6 μm

TABLE 26 % FPF < 5.6 μm Capsule White Clear Time White No Clear No PointCap Cap Cap Cap  30 Min 57% 53% 56% 61%  60 Min 65% 58% 56% 56% 120 Min61% 64% 59% 59% 240 Min 64% 61% 57% 58%

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It should also be understood thatthe embodiments described herein are not mutually exclusive and thatfeatures from the various embodiments may be combined in whole or inpart in accordance with the invention.

What is claimed is:
 1. A capsule for use in an inhalation device filledwith a dry powder comprising levodopa and having a working densitybetween about 0.02 to about 0.1 g/cm³, and containing a capsule shellcomprising hydroxypropyl methylcellulose (HPMC) and titanium dioxide,and wherein said capsule emits more powder comprising levodopa uponactuation of the inhalation device as compare to a capsule thatcomprises HPMC and is free of titanium dioxide.
 2. The capsule of claim1, wherein said working density is between about 0.02 g/cm³ to about0.05 g/cm³.
 3. The capsule of claim 1, wherein said dry powder comprisesfrom about 2 to about 8% of water by weight.
 4. The capsule of claim 3,wherein said dry powder comprises from about 5 to about 6% of water byweight.
 5. The capsule of claim 1, wherein said capsule is a 00 sizecapsule.
 6. The capsule of claim 5, wherein said dry powder comprisesbetween about 15 and 50 milligrams of levodopa.
 7. The capsule of claim6, wherein said dry powder comprises between about 25 and 35 milligramsof levodopa.
 8. The capsule of claim 1, wherein said dry powder furthercomprises a salt.
 9. The capsule of claim 8, wherein said salt is sodiumchloride.
 10. The capsule of claim 8, wherein said dry powder furthercomprises a phospholipid.
 11. The capsule of claim 10, wherein saidphospholipid is dipalmitoylphosphatidylcholine (DPPC).
 12. The capsuleof claim 1 comprising from about 25 to 45 milligrams of dry powdercomprising at least 80% of levodopa by weight, a fine particle fraction(FPF) between 55 to 68% of the nominal dose, and a working densitybetween about 0.02 to about 0.05 g/cm³.
 13. The capsule of claim 1,wherein the dry powder comprises about 85% by weight or more oflevodopa.
 14. The capsule of claim 1, wherein the dry powder comprisesabout 90% by weight or more of levodopa.
 15. The capsule of claim 1,wherein the dry powder comprises a salt and the salt is sodium chloride(NaCl).
 16. The capsule of claim 1, wherein the FPF of the dry powder isabout 50% to about 70% of the nominal dose.
 17. The capsule of claim 1,wherein the capsule is filled with about 20 milligrams or more of thedry powder.
 18. The capsule of claim 1, wherein the capsule is filledwith about 30 to about 50 milligrams of dry powder.
 19. The capsule ofclaim 1, wherein the dry powder composition comprises a weight ratio oflevodopa/DPPC/NaCl of 90:8:2.
 20. The capsule of claim 1, wherein thedry powder comprises about 75% by weight or more levodopa, DPPC and asalt.
 21. The capsule of claim 1, wherein the FPF of the dry powder isabout 50% to about 70% of the nominal dose.